This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Interferon regulatory factor 3 (IRF3) is critical in the induction phase of the IFN response. Its role, however, in the control of replication of certain viruses, including HSV-1, is enigmatic. A number of HSV genes interfere with the localization and function of IRF-3 in vitro, suggesting that IRF-3 is critical for controlling HSV replication. The deficiency ofIRF-3 would therefore be predicted to preclude the function of early recognition pathways and thereby impact HSV-1 replication. Paradoxically,IRF-3 deficient mice (IRF3-/-) show no increased susceptibility to HSV-1,and no changes in HSV replication in primary IRF-3-/- MEFs have been observed. In agreement with this, we have shown that primary MEFs do not exert such control. Other recent preliminary data, however, showed significantly increased growth of HSV in IRF3-/- dendritic cells, suggesting that cells derived from the immune system exert IRF-3 dependent control over HSV replication. We reasoned that there were two possible hypotheses to explain these observations. First, that HSV controls IRF-3 activity so completely that, in certain cells, IRF-3 is rendered redundant. Second, that there is a tissue-specificity to the control of HSV replication in vitro and in vivo, and virulence in vivo by IRF-3- dependent mechanisms. The over-arching goal of this proposal is therefore, to test these hypotheses and distinguish between them. Specific aim 1: To measure and assess the impact of IRF-3- dependent mechanisms upon the replication of HSV in primary cells derived from the immune system in vitro. Specific aim 2: To measure and assess the impact of IRF-3- dependent mechanisms upon the replication and virulence of HSV in mouse models of HSV pathogenesis and latency in vivo.